Abstract: Capsule endoscopy is now recognized as the first line examination for patients with obscure bleeding and in selected patients with various small bowel diseases. A capsule endoscope has been designed for exploring the colon. Two pilot studies and one large multicenter trial have shown that the colon capsule is feasible and safe and provides encouraging data although its sensitivity for detecting colonic polyps is lower than optical colonoscopy. Technological improvements of the capsule and adaptation of the colon preparation are expected to increase the sensitivity of the colon capsule.

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world. The majority of CRC cases are believed to arise from adenomatous polyps that progress over the course of many years to invasive adenocarcinoma (Bond, 2000). Current evidence-based guidelines recommend the screening of average risk adults, since early detection and removal of adenomatous polyps have been shown to reduce both the incidence of colorectal cancer and colorectal cancer-related mortality (Winawer et al., 1993; Winawer and Zauber, 2002). It has been recently emphasized that the primary goal of CRC cancer screening should be the early detection of “advanced” adenomatous polyps which have a higher risk of progression to cancer. A recently published joint guideline from the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology defined the screening tests and screening intervals that may best detect colonic polyps and colorectal cancer. These screening tests include flexible sigmoidoscopy every 5 years, optical colonoscopy (OC) every 10 years, double-contrast barium enema every 5 years, or CT colonography every 5 years (Levin et al., 2008). Such screening can reduce CRC incidence and mortality but its effectiveness depends on its quality, ease of use, and patient adherence (Winawer et al., 1993).

Optical colonoscopy is currently considered to be the gold standard procedure for CRC screening despite some limitations such as the suboptimal performance of colonoscopy and the poor quality of the bowel preparation (Rex and Helbig, 2007; Ponchon, 2007). Moreover, limited endoscopy resources may limit its access to large, population-based screening programs and many individuals are reluctant to undergo optical colonoscopy because of its perceived inconvenience and discomfort. In fact, compliance to CRC screening is only about 50% in the U.S. and typically 20% or lower across Europe (Ponchon, 2007). The main objective of a CRC screening program is to lower the population mortality rate related to this particular tumor. Besides the sensitivity of any method for detecting a lesion, the development of well-accepted and non-invasive and, if possible, less costly methods is mandatory to reach this goal.

About 10 years ago, the development of the small bowel video-capsule endoscopy revolutionized the field of endoscopy in establishing the new concept of wireless endoscopy (Given Imaging, Yoqneam, Israel). In brief, a small capsule containing a camera is swallowed by the patient and it spontaneously progresses throughout the upper GI tract and the small bowel, transmitting images (two per second) which are recorded in an external recording unit that receives the information transmitted by the ingested capsule. The data are downloaded from the recorder to a computer workstation for processing and subsequent viewing.

When this new technology was launched, some people were questioning whether this method would be a new tool or a new toy. Now, the small bowel video-capsule is recognized to be the first line of diagnostic procedure in case of obscure bleeding (Cellier, 2008) and its role has been confirmed in other intestinal diseases such as inflammatory bowel diseases (Bourreille et al., 2009), celiac disease (Rondonotti and de Franchis, 2007), familial adenomatous polyposis (Iaquinto et al., 2008), and other clinical disorders. The appearance of the small bowel video-capsule along with the development of various enteroscopes that have therapeutic capabilities totally changed the approach to the diagnosis of small bowel diseases.

The use of the video-capsule was also extended to the exploration of the esophagus. The main distinguishing feature of the eso-capsule is the presence of a camera at both ends of the capsule capable of emitting 4 images/second, allowing a good visualization of the esophageal mucosa. This device has been mostly assessed in lesions associated with gastroesophageal reflux disease (GERD) and portal hypertension lesions (Waterman and Gralnek, 2009).

Based on the success of the SB capsule and the technical adaptations of the esocapsule, it appears to be challenging to develop a Pillcam® colon capsule endoscope (PCCE) that could be an alternative method for CRC screening. Obviously, the development of a wireless endoscope for exploring the colon raised several challenging questions: 1) the duration of the colon transit time requires an efficient use of batteries; 2) the cleanliness of the colon requires an excellent colon preparation; 3) the calibre of the colon lumen takes into account the impossibility of inflating the colon during a colonoscopy.

Colon Capsule Endoscopy

The PCCE has two imagers at both ends that acquire images at a rate of 4 frames per second (Given Imaging, Yoqneam, Israel). The size of the colon capsule is 31 x 11 mm. In order to conserve battery life, the colon capsule has been designed with a preprogrammed sleeping mode. That means that after 1 h 45 min the capsule is reactivated when the capsule has reached the terminal ileum. The envelope of the PCCE is made of biocompatible materials similar to the initial SB capsule.

Endoscopic images are recorded in a portable recorder which consists of an antenna array that is attached to the body and a receiver. After completion of the examination, data are downloaded from the recorder to the RAPID workstation for processing and subsequent viewing. The selected reading speed is approximately 8 frames per second but may be changed as needed.

Colon Preparation

The colon preparation has been adapted for meeting several objectives: first, to clean the colon as thoroughly as possible; second, to provoke the progression of the capsule throughout the small bowel up to the colon; and third, to provide residual clear liquid in order to facilitate the visualization of the colonic mucosa using the so-called “submarine view.” Patients have to follow a clear liquid diet the day before the procedure. On the evening before the colon capsule ingestion, patients orally ingested 3 liters of polyethylene glycol solution (ColoPEG® or Klean Prep®) and an additional liter between 06:00am and 07:00am on the day of the procedure. Then the patient ingests the capsule after having received two 10 mg Domperidone. Two hours after the capsule ingestion, patients are to orally ingest 45 ml of Sodium Phosphate solution (Fleet Phosphosoda) that serves as a booth for facilitating the capsule progression. The progression of the capsule is assessed with a real time viewing system performed with Rapid Access Real Time Tablet DC (Given Imaging). The quality of the colon cleansing is determined according to a four-point grading scale (excellent, good, fair, and poor) as previously described.

Clinical Studies

The accuracy of the colon capsule for detecting colorectal polyp and cancer was evaluated in two pilot studies (Schoofs et al., 2006; Eliakim et al., 2006). The first study was performed in a single center (Hôpital Erasme, Brussels) (Schoofs et al., 2006). Patients were considered for the study if they were scheduled to undergo colonoscopy for CRC screening or for unexplained abdominal pain or alarm symptoms (including rectal bleeding and altered bowel transit time). The capsule was ingested in the morning. After excretion, the colonoscopy was performed. Significant findings were defined either as polyps > 6 mm, or three or more polyps of any size. All detected polyps were recorded as positive findings. Colonoscopy and colon capsule endoscopy reviews were performed by independent physicians. In this study, results from 36 patients were analyzed. CCE identified 19 of the 25 patients (76%) with positive findings and 10 of the 13 (77%) with significant lesions detected by colonoscopy. Overall, sensitivity of PCCE for detecting significant lesions was 77%, specificity was 70%, and the negative predictive value reached 84%.

In the second pilot study, the PCCE was tested in a multicenter setting (Eliakim et al., 2006). Study subjects underwent colon preparation and then ingested the capsule in the morning of the examination day, with conventional colonoscopy being performed on the same day. The PCCE findings were reviewed by three experts in capsule endoscopy who were blinded to the conventional colonoscopy findings.

A total of 91 patients were enrolled in three Israeli centers and the results were evaluable in 84 cases. Polyps of any size were found in 45 patients, with 34 out of 45 (76%) being found by the capsule and 36 out of 45 (80%) by conventional colonoscopy. Interestingly, the authors showed that sensitivity of the PCCE for detecting polyps based upon the principal investigators’ reading (56%) improved when the reading was done by 3 experts (76%) and suggested that there was likely to be a learning curve for reading capsule endoscopy videos of the colon.

Recently, a prospective, multicenter study comparing CCE to optical colonoscopy was performed in 328 adults (mean age: 58.6, from 22 to 84 years) with known or suspected lesions for the detection of colorectal polyps or cancer (Van Gossum et al., 2009). The OC was considered as the gold standard against which PCCE was compared.

Patients underwent the colon preparation that was tested in the 2 previous pilot studies. As we described, this colon preparation included a clear diet the day before, the ingestion of polyethylene glycol solution the day before and in the morning, as well as the ingestion of a booth of Phosphosoda.

At 1:45 hours post-ingestion (upon “wake-up”) the capsule remained proximal to the cecum in 97.5% of the patients. Sixty-nine percent of the patients excreted the capsule within 6 hours post-ingestion and 92.8% within 10 hours. The median residence time in the colon was 1.18 hours (range 0.04 to 7.57 hours) and the median GI tract transit time (from mouth to anus) was 4.01 hours (range 2.05 to 10.00 hours).

Colon cleanliness was considered to be good-to-excellent in 72% of patients for PCCE and in 87% for conventional optical colonoscopy. In this cohort of 320 patients who were included in the accuracy analysis, 68% of the patients had at least one polyp, the majority being less than 6 mm in size. Fifty patients (16%) had at least one polyp equal or greater than 10 mm. OC detected 23 invasive carcinomas in 19 patients. Twenty two of the 23 invasive carcinomas measured greater than 10 mm.

The sensitivity and specificity of PCCE for detecting polyps that were 6 mm in size or bigger were 64% and 84%, respectively, and for detecting advanced adenoma, the sensitivity and specificity were 73% and 79%, respectively. Of the 19 patients with cancer detected by colonoscopy, 14 were detected by the CEE (sensitivity: 74%). Interestingly, the sensitivity was significantly higher in the patients with good-to-excellent cleanliness (72% of the global population) as compared with the patients with poor or fair cleanliness, with a limited effect on specificity.

For patients with advanced adenoma, the sensitivity and specificity in the 33 patients with good-to-excellent cleanliness were 88% and 78%, respectively. The 2 pilot studies and the large multicenter trial comparing the accuracy of PCEE to conventional colonoscopy for detecting colon polyps and cancer have shown that colon capsule endoscopy is feasible and safe (Schoofs et al., 2006; Eliakim et al., 2006; Van Gossum et al., 2009). However, the sensitivity of PCEE for detecting polyps is lower than optical colonoscopy. Interestingly, the sensitivity of PCEE significantly increased in the group of patients with a good to excellent colon preparation.

Our results for detecting polyps > 10 mm are inferior to those reported with CT colonography (virtual colonoscopy) in which the sensitivity for detecting lesions at least 10 mm was 93.8% and the specificity for same size lesions reached 96%, in a average-risk screening population (Pickhardt et al., 2003; Kim et al., 2007). However, at this time, it may be inappropriate to compare PCCE to virtual colonoscopy. First, this present trial was not a comparative study comparing PCCE to CT colonography. Second, if we refer to the initial test characteristics reported for CT colonography at the beginning of that method, the results were encouraging, but were not as good as those observed in this first multicenter study using PCCE (Fenlon et al., 2000; Johnson et al., 2003). Along this line, it may be important to underline that 7 of the 8 participating centers were at the beginning of their experience when the study was started.

Conclusion

What can we learn from these clinical studies about the use of colon capsule endoscopy? Although PCCE cannot yet be recommended as a screening procedure for CRC, data are very encouraging. Indeed this method is minimally invasive, safe and can be performed on an ambulatory basis. These clinical studies provide data to support the potential role of PCCE in the future in the armamentarium of techniques aiming to visualize colon polyps and colorectal cancers. Capsule colonoscopy could have already been considered as an alternative for patients unwilling to undergo OC or for those in whom OC was incomplete or contraindicated. Potential additional advantages of PCCE might be that it can perform a complete evaluation of the GI tract including screening for Barrett’s esophagus as was suggested in one of the pilot studies (Schoofs et al., 2006). Since the population at risk for esophageal cancer and colorectal polyps and cancer are in the same age range, this could provide a more efficient and economical method of screening for both conditions and may be of interest for further evaluation. Improvements in the definition of the best colon preparation regimen are eagerly expected, so as studies comparing PCCE to OC and CT colonography in average risk screening populations. If further improved, capsule colonoscopy may have the potential for dramatically increasing population compliance to CRC screening by offering a minimally invasive screening method for polyps and cancers, which could be performed outside of the typical medical offices, potentially even in an “in home” setting with the goal of “liberating” medical resources in GI for the performance of therapeutic endoscopic examinations. Protocols with a second generation PCCE and a newly improved colon preparation are currently ongoing.